Abstract P2-03-14: Tumor-agnostic measurement of ctDNA levels in first line ER+, HER2- metastatic breast cancer patients as a marker for survival
Authors: Noortje Verschoor, Jaco Kraan, Vanja de Weerd, Ngoc M Van, Agnes Jager, Stefan Sleijfer, John WM Martens, Saskia M Wilting
Journal: Cancer Research (2023)

Abstract INTRODUCTION: Circulating tumor cell (CTC) count and levels of circulating tumor DNA (ctDNA) have proven their individual prognostic value in metastatic breast cancer (MBC). Whereas CTCs can be quantified by enumeration, levels of ctDNA are often expressed as the variant allele frequency of the dominant mutation. The modified fast aneuploidy screening test-sequencing system (mFAST-SeqS) estimates ctDNA-load by measuring chromosomal aneuploidy instead of mutations. The mFAST-SeqS method is cheap and provides a comprehensive overview of the tumor genome without prior knowledge on genomic tumor aberrations. Previously, we showed in a small MBC cohort (n=50), heterogeneous with regard to subtype and line of treatment, that the mFAST-SeqS-derived genome-wide aneuploidy score (GWA-score) was an independent prognostic biomarker (1). Our current aim was to provide evidence for the prognostic value of GWA-score in a homogeneous cohort of estrogen receptor positive (ER+), HER2 negative (HER2-) MBC patients, starting first line treatment with an aromatase inhibitor. MATERIALS &amp; METHODS: CTCs were enumerated using the CellSearch-system (Menarini) and screened for ctDNA fraction using mFAST-SeqS in ER+, HER2- MBC patients, starting with first line aromatase inhibitors. CTC-count was divided into high (CTChigh) and low (CTClow) using the validated cut-off of 5 CTCs/7.5 ml blood; similarly GWA-score was divided in high (GWAhigh)and low (GWAlow) based on the previously described cut-off of 5 (2). PFS and OS were estimated using Kaplan-Meier. Cox regression was used for uni- and multivariable analysis. RESULTS: One hundred and thirty-four patients were included in this analysis. Mean age was 68 (range 40-90). Median follow up was 26 months. Sixty-five samples had both scores low and 30 both high, 25 samples were CTChigh/GWAlow and 14 were CTClow/GWAhigh. PFS and OS were not significantly different between CTChigh versus CTClow groups (p=0.07 and p=0.26, median PFS 15 vs 24 months, median OS 45 vs 49 months). However, PFS and OS were significantly different between GWAhigh versus GWAlow groups (p &amp;lt; 0.01 for both, median PFS 11 vs 24 months, median OS 31 vs 51 months). In multivariate analysis, GWA-score was a significant prognostic factor for both PFS and OS while presence of visceral disease was also prognostic for OS (table 1). CONCLUSIONS: In patients treated with aromatase inhibitors in the first line of treatment, GWA-score was an independent prognostic marker for a worse PFS and OS and may have added value beyond CTC-count. 1. Verschoor, N., et al., Abstract P2-01-17: Circulating tumor cell count and levels of circulating tumor DNA are complementary prognostic biomarkers in metastatic breast cancer - A pilot study. Cancer Research, 2022. 82(4_Supplement): p. P2-01-17-P2-01-17. 2. Belic, J., et al., mFast-SeqS as a Monitoring and Pre-screening Tool for Tumor-Specific Aneuploidy in Plasma DNA. Adv Exp Med Biol, 2016. 924: p. 147-155. Table 1: Uni- and multivariate Cox regression for PFS and OS Citation Format: Noortje Verschoor, Jaco Kraan, Vanja de Weerd, Ngoc M Van, Agnes Jager, Stefan Sleijfer, John WM Martens, Saskia M Wilting. Tumor-agnostic measurement of ctDNA levels in first line ER+, HER2- metastatic breast cancer patients as a marker for survival [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-03-14.